Endoscopic retrograde cholangiopancreatography in cirrhosis - a systematic review and meta-analysis focused on adverse events

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Gastrointestinal Endoscopy
World J Gastrointest Endosc 2018 November 16; 10(11): 322-377
ISSN 1948-5190 (online)
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Contents Monthly Volume 10 Number 11 November 16, 2018
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EDITORIAL
322 Screeningforcolorectalcancerinpatientswithinammatoryboweldisease.Shouldwealreadyperform
chromoendoscopyinallourpatients?
Huguet JM, Suárez P, Ferrer-Barceló L, Iranzo I, Sempere J
REVIEW
326 Stepwiseevaluationofliversectorsandliversegmentsbyendoscopicultrasound
Sharma M, Somani P, Rameshbabu CS, Sunkara T, Rai P
ORIGINAL ARTICLE
Observational Study
340 Polysomnographicassessmentofrespiratorydisturbanceduringdeeppropofolsedationforendoscopic
submucosaldissectionofgastrictumors
Urahama R, Uesato M, Aikawa M, Yamaguchi Y, Hayano K, Matsumura T, Arai M, Kunii R, Isono S, Matsubara H
Prospective Study
348 Submucosalinjectionofplatelet-richplasmainendoscopicresectionoflargesessilelesions
Lorenzo-Zúñiga V, Moreno de Vega V, Bartolí R, Marín I, Caballero N, Bon I, Boix J
META-ANALYSIS
354 Endoscopicretrogradecholangiopancreatographyincirrhosis-asystematicreviewandmeta-analysis
focusedonadverseevents
Mashiana HS, Dhaliwal AS, Sayles H, Dhindsa B, Yoo JW, Wu Q, Singh S, Siddiqui AA, Ohning G, Girotra M, Adler DG
CASE REPORT
367 Tightnear-totalcorrosivestricturesoftheproximalesophaguswithconcomitantinvolvementofthe
hypopharynx:Flexibleendoscopicmanagementusinganoveltechnique
Dhaliwal HS, Kumar N, Siddappa PK, Singh R, Sekhon JS, Masih J, Abraham J, Garg S

Contents World Journal of Gastrointestinal Endoscopy
Volume 10 Number 11 November 16, 2018
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AIM AND SCOPE
INDEXING/ABSTRACTING

Harmeet Singh Mashiana, Amaninder Singh Dhaliwal, Harlan Sayles, Banreet Dhindsa, Ji Won Yoo, Qing Wu,
Shailender Singh, Ali A Siddiqui, Gordon Ohning, Mohit Girotra, Douglas G Adler
META-ANALYSIS
354 November 16, 2018
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Endoscopic retrograde cholangiopancreatography in
cirrhosis - a systematic review and meta-analysis focused
on adverse events
Harmeet Singh Mashiana, Banreet Dhindsa, Ji Won Yoo,
Department of Internal Medicine, University of Nevada Las
Vegas School of Medicine, Las Vegas, NV 89102, United States
Amaninder Singh Dhaliwal, Shailender Singh, Division
of Gastroenterology and Hepatology, University of Nebraska
Medical Center, 982000 Nebraska Medical Center, Omaha, NE
68198-2000, United States
Harlan Sayles, Department of Biostatistics, University of
Nebraska Medical Center, 982000 Nebraska Medical Center,
Omaha, NE 68198-2000, United States
Qing Wu, Nevada Institute of Personalized Medicine, Department
of Environmental and Occupational Health, School of Community
Health Sciences, University of Nevada, Las Vegas, NV 89154-4009,
United States
Ali A Siddiqui, Division of Gastroenterology, Jefferson Medical
College, Philadelphia, PA 19107, United States
Gordon Ohning, Division of Gastroenterology, University of
Nevada Las Vegas School of Medicine, Las Vegas, NV 89102,
United States
Mohit Girotra, Division of Gastroenterology, University of
Miami Miller School of Medicine, Miami, FL 33136, United
States
Douglas G Adler, Division of Gastroenterology and Hepatology,
University of Utah School of Medicine, Huntsman Cancer
Center, Salt Lake City, UT 84132, United States
ORCID number: Harmeet Singh Mashiana (0000-0002-90
19-7657); Amaninder Singh Dhaliwal (0000-0002-9761-437X);
Harlan Sayles (0000-0002-4082-8289); Banreet Dhindsa (00
00-0002-9858-0941); Ji Won Yoo (0000-0002-3790-1596);
Qing Wu (0000-0001-9407-5617); Shailender Singh (0000-00
01-8596-2927); Ali A Siddiqui (0000-0002-0879-2589); Gordon
Ohning (0000-0002-9252-7023); Mohit Girotra (0000-0002-
7086-7211); Douglas G Adler (0000-0003-3214-6285).
Submit a Manuscript: http://www.f6publishing.com
DOI: 10.4253/wjge.v10.i11.354
World J Gastrointest Endosc 2018 November 16; 10(11): 354-366
ISSN 1948-5190 (online)
Author contributions: Mashiana HS contributes to literature
search, quality assessment, data collection, manuscript preparation;
Dhaliwal AS contributes to literature search, data collection;
Sayles H is the statistician; Banreet Dhindsa B contributes to
data collection, manuscript preparation, and final edit of the
manuscript; Yoo JW contributes to manuscript preparation and
biostatistics; Wu Q, Singh S, Siddiqui AA, Ohning G, and Girotra
M contributes to manuscript preparation and final editing;
and Adler DG contributes to preparation and final edit of the
manuscript.
Conict-of-interest statement: All authors have no conicts of
interest to report.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Douglas G Adler, MD, FACG, AGAF,
FASGE, Professor, Division of Gastroenterology and Hepatology,
University of Utah School of Medicine, Huntsman Cancer
Center, 30 N 1900 E, Room 4R118, Salt Lake City, UT 84132,
United States. douglas.adler@hsc.utah.edu
Telephone: +1-801-5817878
Fax: +1-801-5818007
Received: February 28, 2018
Peer-review started: February 28, 2018
First decision: July 9, 2018
Revised: July 17, 2018
Accepted: August 21, 2018
Article in press: August 21, 2018
Published online: November 16, 2018

Abstract
AIM
To investigate indications and outcomes of endos-
copic retrograde cholangiopancreatography (ERCP)
in cirrho ti cs , especially ad verse events. Patien ts
with cirrhosis undergoing ERCP are believed to have
increased risk. However, there is a paucity of literature
describing the indi cations and outcomes of ERCP
procedures in patients with cirrhosis, especially focusing
on adverse events.
METHODS
We performed a systematic appraisal of major literature
databases, including PubMed and EMBASE, with a
manual search of literature from their inception until
April 2017.
RESULTS
A total of 6,505 patients from 15 studies were analyzed
(male ratio 59%, mean age 59 years), 11% with
alcoholic and 89% with non-alcoholic cirrhosis, with
56.2% Child-Pugh class A, and 43.8% class B or C.
Indic ations for ERCP included chole docholithias is
60.9%, biliary strictures 26.2%, gallstone pancreatitis
21.1% and cholangitis 15.5%. Types of interventions
included endoscopic sphincterotomy 52.7%, biliary
stenting 16.7% and biliary dilation 4.6%. Individual
adverse events included hemorrhage in 4.58% (95%CI:
2.77-6.75%,
I
2 = 85.9%), post-ERCP pancreatitis
(PEP) in 3.68% (95%CI: 1.83-6.00%,
I
2 = 89.5%),
cholangitis in 1.93% (95%CI: 0.63-3.71%,
I
2 = 87.1%)
and perforation in 0.00% (95%CI: 0.00-0.23%,
I
2 =
37.8%). Six studies were used for comparison of ERCP-
related complications in cirrhosis
vs
non-cirrhosis, which
showed higher overall rates of complications in cirrhosis
patients with pooled OR of 1.63 (95%CI: 1.27-2.09,
I
2
= 65%): higher rates of hemorrhage with OR of 2.05
(95%CI: 1.62-2.58,
I
2 = 2.1%) and PEP with OR of 1.33
(95%CI: 1.04-1.70,
I
2=65%), but similar cholangitis
rates with OR of 1.23 (95%CI: 0.67-2.26,
I
2 = 44.3%).
CONCLUSION
There is an overall higher rate of adverse events
related to ERCP in patients with cirrhosis, especially
hemorrhage and PEP. A thorough risk/benefit assess-
ment should be performed prior to undertaking ERCP in
patients with cirrhosis.
Key wo rds: Meta-analysis; Endo scopic retrograde
cholangiopancreatography; Systematic review; Adverse
events; Cirrhosis
© The Author(s) 2018. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Patients with cirrhosis undergoing endoscopic
retrograde cholangiopancreatography (ERCP) are
considered to have increased risk. However, there is
a paucity of literature describing the indications and
outcomes of ERCP procedures in these patients. Our
355
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Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis
meta-analysis included 6,505 patients from 15 studies,
with indications including choledocholithiasis, biliary
strictures, gallstone pancreatitis and cholangitis. Types
of interventions included sphincterotomy, stenting and
dilation. Individual adverse events included hemo-
rrhage, post-ERCP pancreatitis (PEP), and cholangitis.
Comparison of ERCP-related complications in cirrhosis
vs
non-cirrhosis suggested higher overall rates of com-
plications in cirrhosis patients with pooled (especially
hemorrhage and PEP) but similar cholangitis rates.
Mashiana HS, Dhaliwal AS, Sayles H, Dhindsa B, Yoo JW,
Wu Q, Singh S, Siddiqui AA, Ohning G, Girotra M, Adler DG.
Endoscopic retrograde cholangiopancreatography in cirrhosis - a
systematic review and meta-analysis focused on adverse events.
World J Gastrointest Endosc
2018; 10(11): 354-366 Available
from: URL: http://www.wjgnet.com/1948-5190/full/v10/i11/354.
htm DOI: http://dx.doi.org/10.4253/wjge.v10.i11.354
IntroductIon
Endoscopic retrograde cholangiopancreatography
(ERCP) is one of the most commonly performed
endoscopic procedures and is known for its high-risk
nature[1]. Performing ERCP in patients with cirrhosis
is not only challenging, but may even be a high-risk
procedure in this setting[2]. There is a known increased
incidence of gallstones and choledocholithiasis in pa-
tients with cirrhosis, potentially requiring frequent ERCP
procedures[2,3]. ERCP inherently carries risks of usual
adverse events, including post-ERCP pancreatitis (PEP),
hemorrhage, infection, perforation, and anesthesia-
related events[4]. In addition, risks of adverse events
in patients are believed to be higher in patients with
cirrhosis requiring ERCP due to a poor synthetic function
of the liver and resulting portal hypertension, ascites,
varices, coagulopathy, and encephalopathy[5].
Surgery may not always be an option for pan-
creatobiliary disorders in patients with cirrhosis because
of the high rates of morbidity and mortality due to
underlying liver disease. As a general rule, minimally-
invasive approaches, including ERCP, are favored in
these patients[6]. Even though the increased risk of
ERCP-related adverse events in cirrhosis patients is
recognized, there is a relative paucity of literature,
as well as some conflicting literature, describing the
indications and outcomes of ERCP procedures in patients
with cirrhosis.
We thus performed the present systematic review
to evaluate the ERCP indications and characteristics,
as well as a meta-analysis of ERCP outcomes in
patients with cirrhosis. The important outcomes that
we focused upon include pooled incidence rates of
patient characteristics, ERCP indications, ERCP-related
interventions and individual ERCP-related adverse
events: (1) hemorrhage; (2) PEP; (3) cholangitis; and
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(4) perforation. The secondary outcomes included a
comparison of ERCP complications in cirrhosis vs non-
cirrhosis patients with pooled odds ratio (OR).
MaterIals and Methods
The preferred reporting items for systematic reviews
and meta-analyses statement and the meta-analysis
of observational studies in epidemiology guidelines
were followed[7,8]. The objectives, primary outcomes,
search strategy, inclusion criteria, and methods for study
selection, data extraction, and data synthesis of this
meta-analysis were defined in a protocol in advance.
Data fields were pre-defined, and sensitivity analysis
and subgroup analysis were also pre-specified in the
protocol.
Search strategy
We performed a literature search using the keywords
“endoscopic retrograde cholangiopancreatography”,
“ERCP”, “cirrhosis”, “adverse events”, or “complications”
in various combinations to identify original studies
published from MEDLINE using both Ovid and PubMed
without language restrictions. Other databases that
were explored included EMBASE and Scopus. The
reference lists of included papers and related review
articles were manually searched. A literature search
was conducted by two authors (HSM and ASD) in
consultation with an experienced medical librarian.
Inclusion and exclusion criteria
We included original prospective, cohort, retrospective,
case-control and, when possible, randomized control
studies that evaluated the ERCP complications in
cirrhosis patients. We also included the studies that
provided a comparison of ERCP complications in
cirrhosis and non-cirrhosis patients. We included the
studies in English and any studies in other languages
found through the manual search of references from
inception until April 2017. We excluded studies that
described the ERCP complications only in non-cirrhosis
patients, and did not define clearly the number of
ERCPs or their outcomes.
Study selection and data extraction
In the initial screening stage, simple relevance cri-
teria were employed for study selection: (1) human
participants; and (2) ERCP complications in cirrhosis
patients as an outcome measure. Each title and abstract
of the articles obtained through the electronic search
was independently reviewed by two investigators (HSM
and ASD). Citations were excluded only if deemed to
be obviously irrelevant by both reviewing investigators,
however those with reviewer disagreement were included
for full review.
In the second stage of study selection, the full
content of each article obtained during the screening
stage was reviewed and evaluated. Using predetermined
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selection criteria and assessment methods, two in-
vestigators (HSM and ASD) independently evaluated
the full content of each English language article. Articles
in other languages were reviewed and evaluated by
multilingual investigators as well as google translation
tools using the same criteria and assessment methods.
We included studies that reported the ERCP com-
plications in cirrhosis patients and that described hazard
ratio (HR), relative risk (RR), or OR of comparison of ERCP
complications in cirrhosis and non-cirrhosis patients. In
addition, cohort and case-control studies that reported
data on ERCP complications in cirrhosis patients were
included if no related randomized controlled trials were
found.
Twenty-one studies relevant to the inclusion criteria
were identied. The actual numbers of ERCP cases were
collected from tables and manuscript text in each study.
Since data was from previously published studies, an
institutional review board approval was waived. Figure 1
presents the study selection process in accordance with
the preferred reporting items for systematic reviews and
meta-analyses statement[7]. A summary of studies is
shown in Table 1. After excluding six studies for various
reasons, including unclear information on a number
of ERCPs, outcomes, consensus statements or ERCP
in congenital malformation patents, 15 studies were
selected for final analysis. These 15 studies included
the six studies that were separately used to perform
a subset analysis to compare ERCP adverse events in
cirrhosis and non-cirrhosis patients.
Data from the eligible studies were independently
abstracted by the two investigators (HSM and BD)
using the Microsoft Excel program. Any disagreement or
uncertainty was resolved by discussion and rechecking
original articles, and, if still unresolved, then contacting
the authors and consulting external experts. Information
such as authors, title, published year, country of study,
study design, sample size, and sampling methods,
socio-demographic characters such as age, sex, race,
exposures and their measurement methods, outcomes
and their validation methods, duration of follow-up,
adjusted risk factors, and HR or RR of ERCP in cirrhosis
and non-cirrhosis patients were duly recorded.
Data synthesis and analysis
The overall proportions of patients experiencing any
post-procedure adverse events or specic complications
were estimated using random effects methods designed
for the pooling of proportions. The actual proportions
were estimated after the Freeman-Tukey double arcsine
transformation had been applied to the individual study
proportions and standard errors were calculated using
the scoring method[9,10]. For the subset of studies that
provided separate reports of adverse events for patients
with or without cirrhosis, we combined individual study
results to calculate the pooled OR and 95% condence
intervals (CI) using random-effects meta-analysis for a
dichotomous outcome[11]. Between-study heterogeneity
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et al
. Meta-analysis of ERCP in cirrhosis

was assessed using the I2 statistic, which is an estimate
of the percentage of variation across studies that is due
to true heterogeneity and not due to chance[12]. Baseline
characteristics of study participants were aggregated
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from 15 analyzed studies as shown in Table 2. All
analyses were performed using STATA version 14.2
(StataCorp, College Station, TX). A two-sided p-value <
0.05 was considered statistically signicant.
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Ref. Yr of publication Country Study type Cohort/ Case-control Yr No. of patients
Navaneethan et al[5] 2017 United States Retrospective Case-control 2010 3228
Jagtap et al[20] 2017 India Retrospective Cohort 2014-2016 134
Adler et al[16] 2016 United States Retrospective Cohort 2003-2014 328
Inamdar et al[13] 2016 United States Retrospective Case-control 2009 1930
Gill et al[14] 2016 Pakistan Retrospective Case-control 2008-2014 100
Churrango et al[24] 2016 United States Retrospective Cohort 2008-2015 194
Leal et al[19] 2015 Spain Retrospective Case-control 2002-2014 158
Zhang et al[2] 2015 China Retrospective Cohort 2000-2014 77
Li et al[17] 2014 China Retrospective Cohort 2000-2008 46
Ma et al[22] 2013 China Retrospective Cohort 2002-2013 41
Artifon et al[21] 2011 Brazil Prospective Case-control Not specied 105
Park et al[18] 2004 South Korea Prospective/Retrospective Case-control 1998-2003 41
Prat et al[25] 1996 France Retrospective Cohort 1988-1993 52
Freeman et al[23] 1995 United States Prospective Case-control Not specied 64
Sugiyama et al[15] 1993 Japan Prospective Cohort Not specied 7
Table 1 Description of 15 studies used in the nal analysis
Databases from their inception through
April 30, 2017
Embase (
n
= 136) PubMed (
n
= 80)
Manual search of
references and
conference proceedings
(
n
= 6)
Excluded (
n
= 176)
Duplicates
Excluded (
n
= 24)
Case report series (
n
= 12)
Conference consensus (
n
= 1)
Review/meta-analysis (
n
= 7)
Age < 18-year-old (
n
= 4)
Excluded (
n
= 5)
Unclear number of ERCP's (
n
= 2)
Unclear outcomes (
n
= 2)
Limited to congenital
malformation (
n
= 1)
Titles and abstracts were
screened (
n
= 222)
Abstracts were reviewed
(
n
= 44)
Full text screened for
eligibility (
n
= 20)
Studies for systematic
review (
n
= 15)
IDENTIFICATION
SCREENING
ELIGILBILITY
INCLUDED
Figure 1 Study selection process in accordance with preferred reporting items for systematic reviews and meta-analysis statement.
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

Quality assessment
The Newcastle–Ottawa score was used to assess the
quality of nonrandomized studies by two authors (BD
and HSM). Any discrepancies were resolved by a third
reviewer (DGA).
results
A total of 6505 patients from 15 studies were analyzed.
A description of the studies is reported in Table 1.
Adverse events secondary to ERCP in these patients are
reported in Table 3. From the demographic information
that was provided in various studies, male ratio was
59% and mean age was 59.26 years in ten studies.
Out of the nine studies that described the etiology of
cirrhosis, 11% had alcoholic cirrhosis and 89% had non-
alcoholic causes. Data from 13 studies described 56.2%
of the patients belonging to Child-Pugh class A, and the
remainding 43.8% were Child-Pugh class B or C.
A total of 6735 ERCP procedures were performed.
The indications for the ERCP included choledocholithiasis
in 60.9% (4006/6571) of the procedures in 13
studies, cholangitis 15.5% (1021/6571) in 13 studies,
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biliary strictures 26.2% (1740/6635) in 14 studies
and gallstone pancreatitis 21.1% (916/4338) in nine
studies. The type of intervention during the ERCP was
described in ten studies, which included endoscopic
sphincterotomy in 52.7% of the procedures, biliary
stenting in 16.7% and biliary dilation in 4.6% of the
cases.
The individual adverse event rates were as follows:
incidence of ERCP-related hemorrhage in 15 studies
was 4.58% (95%CI: 2.77-6.75%, p < 0.01, I2 =
85.92%) (Figure 2A), PEP in 14 studies was 3.68%
(95%CI: 1.83-6.00%, p < 0.01, I2 = 89.50%) (Figure
2B), cholangitis in 13 studies was 1.93% (95%CI:
0.63-3.71%, p < 0.01) (Figure 2C) and perforation in
13 studies was 0.00% (95%CI: 0.00-0.23%, p = 0.08,
I2 = 37.8%) (Figure 2D).
Six out of 15 studies also compared adverse events
in cirrhosis vs non-cirrhosis patients. Table 3 provides
a description of the studies used for comparing the
adverse events. Figure 2E looks at the meta-analysis
of the comparison of overall complications in these
six studies. Patients with cirrhosis had higher overall
rates of complications compared to non-cirrhosis
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Ref. Yr published Country Study period Study type
Navaneethan et al[5] 2017 United States 2010 Retrospective (NIS), Multicenter
Inamdar et al[13] 2016 United States 2009 Retrospective (NIS), Multicenter
Gill et al[14] 2016 Pakistan 2008-2014 Retrospective, Single center
Leal et al[19] 2015 Spain 2002-2014 Retrospective, Single center
Li et al[17] 2014 China 2000-2008 Retrospective, Single center
Freeman et al[23] 1995 United States NS Retrospective, Multicenter
Table 2 Description of studies used for comparison meta-analysis
Ref. Total no. of patients (cirrhotics) Number of ERCPs PEP Hemorrhage Cholangitis Perforation % of complications
Navaneethan et al[5] 3228 3228 387168110 6 14.5
Jagtap et al[20] 134 134 214110 0 11.9
Adler et al[16] 328 538 2516115 2 14.6
Inamdar et al[13] 1930 1930 160144115 N/A 11.3
Gill et al[14] 100 100 31613 0 12
Churrango et al[24] 194 194 3151N/A 0 4.1
Leal et al[19] 158 158 719110 1 17
Zhang et al[2] 77 77 422421 0 37.6
Li et al[17] 46 46 43233 0 19.5
Ma et al[22] 41 41 04240 0 4.8
Artifon et al[21] 105 105 35750 5 14.2
Park et al[18] 41 41 36664 0 31.7
Prat et al[25] 52 52 01313 1 13.4
Freeman et al[23] 64 64 N/A151N/A N/A 7.8
Sugiyama et al[15] H/B 7 0* 0* 0 0 0
Table 3 Endoscopic retrograde cholangiopancreatography-related adverse events in cirrhosis patients
1PEP and bleeding denitions not clear. Most authors used standard accepted criteria for both; 2PEP: typical pancreatic pain without perforation and the
level of amylase increased to ≥ 3 ULN after the procedure. Bleeding: hematemesis and/or melena, level of postoperative hemoglobin decreased by > 2
g/dL, or requirement of transfusion therapy; 3PEP: (1) new or worsened abdominal pain; (2) new or prolongation of hospitalization for at least 2 d; and
(3) serum amylase ≥ 3 ULN, measured more than 24 h after the procedure. Bleeding: melena and/or hematemesis; 4PEP: Symptoms + Amylase > 500.
Bleeding same as 2; 5PEP: (1) New or worse typical pain (epigastric radiating to the back) associated with tenderness to palpation; (2) Elevation of serum
amylase or lipase ≥ 3 ULN; (3) Both (1) and (2) persist for 24 h after the ERCP. Bleeding: Not adequately dened; 6PEP: Amylase ≥ 3 ULN the morning
after procedure + Symptoms. Bleeding: presence of clinical (not just endoscopic) evidence of bleeding, such as melena or hematemesis, with an associated
decrease of at least 2 g/dL in the Hb concentration, or the need for a blood transfusion. ERCP: Endoscopic retrograde cholangiopancreatography; PEP:
Post-ERCP pancreatitis; N/A: Not available.
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

359WJGE
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www.wjgnet.com November 16, 2018
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Volume 10
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Issue 11
|
Study
Adler (2003-2014)
Artifon (Not specied)
Churrango (2008-2015)
Freeman (Not specied)
Gill (2008-2014)
Inamdar (2009)
Jagtap (2014-2016)
Leal (2002-2014)
Li (2000-2008)
Ma (2002-2013)
Navaneethan (2010)
Park (1998-2003)
Prat (1988-1993)
Sugiyama (Not specied)
Zhang (2000-2014)
Overall (
I
2 = 85.92%,
P
= 0.00)
1.12 (0.51, 2.41)
6.67 (3.27, 13.13)
2.58 (1.11, 5.89)
7.81 (3.38, 17.02)
6.00 (2.78, 12.48)
2.28 (1.70, 3.05)
2.99 (1.17, 7.42)
5.70 (3.03, 10.47)
4.35 (1.20, 14.53)
4.88 (1.35, 16.14)
2.11 (1.67, 2.66)
14.63 (6.88, 28.44)
5.77 (1.98, 15.64)
0.00 (0.00, 35.43)
31.17 (21.93, 42.20)
4.58 (2.77, 6.75)
9.54
6.97
8.23
5.74
6.85
10.21
7.51
7.85
4.89
4.59
10.32
4.59
5.20
1.29
6.21
100.00
538
105
194
64
100
1930
134
158
46
41
3228
41
52
7
77
#
% with # of
ES (95%CI) Weight Hemorrhage ERCPS
6
7
5
5
6
44
4
9
2
2
68
6
3
0
24
10 20 30 40 50
Percentage
Hemorrhage cases per ERCP
A
Study
Adler (2003-2014)
Artifon (Not specied)
Churrango (2008-2015)
Gill (2008-2014)
Inamdar (2009)
Jagtap (2014-2016)
Leal (2002-2014)
Li (2000-2008)
Ma (2002-2013)
Navaneethan (2010)
Park (1998-2003)
Prat (1988-1993)
Sugiyama (Not specied)
Zhang (2000-2014)
Overall (
I
2 = 89.50%,
P
= 0.00)
#
% with # of
ES (95%CI) Weight Pancreatitis ERCPS
10 20 30 40 50
Percentage
Pancreatitis cases per ERCP
4.65 (3.17, 6.77)
2.86 (0.98, 8.07)
1.55 (0.53, 4.45)
3.00 (1.03, 8.45)
8.29 (7.14, 9.60)
1.49 (0.41, 5.28)
4.43 (2.16, 8.86)
8.70 (3.43, 20.32)
0.00 (0.00, 8.57)
11.99 (10.91, 13.15)
7.32 (2.52, 19.43)
0.00 (0.00, 6.88)
0.00 (0.00,35.43)
5.19 (2.04, 12.61)
3.68 (1.83, 6.00)
9.63
7.49
8.57
7.39
10.14
7.96
8.25
5.54
5.25
10.23
5.25
5.85
1.62
6.81
100.00
25
3
3
3
160
2
7
4
0
387
3
0
0
4
538
105
194
100
1930
134
158
46
41
3228
41
52
7
77
B
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

360WJGE
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www.wjgnet.com November 16, 2018
|
Volume 10
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Issue 11
|
Study
Adler (2003-2014)
Artifon (Not specied)
Gill (2008-2014)
Inamdar (2009)
Jagtap (2014-2016)
Leal (2002-2014)
Li (2000-2008)
Ma (2002-2013)
Navaneethan (2010)
Park (1998-2003)
Prat (1988-1993)
Sugiyama (Not specied)
Zhang (2000-2014)
Overall (
I
2 = 87.16%,
P
= 0.00)
#
% with # of
ES (95%CI) Weight Cholangitis ERCPS
10 20 30 40 50
Percentage
Cholangitis cases per ERCP
2.79 (1.70, 4.55)
0.00 (0.00, 3.53)
3.00 (1.03, 8.45)
0.78 (0.47, 1.28)
7.46 (4.10, 13.19)
6.33 (3.47, 11.26)
6.52 (2.24, 17.50)
0.00 (0.00, 8.57)
0.31 (0.17, 0.57)
9.76 (3.86, 22.55)
5.77 (1.98, 15.64)
0.00 (0.00,35.43)
1.30 (0.23, 7.00)
1.93 (0.63, 3.71)
11.03
8.11
7.98
11.78
8.73
9.12
5.72
5.38
11.90
5.38
6.09
1.53
7.25
100.00
15
0
3
15
10
10
3
0
10
4
3
0
1
538
105
100
1930
134
158
46
41
3228
41
52
7
77
C
Study
Adler (2003-2014)
Artifon (Not specied)
Churrango (2008-2015)
Gill (2008-2014)
Jagtap (2014-2016)
Leal (2002-2014)
Li (2000-2008)
Ma (2002-2013)
Navaneethan (2010)
Park (1998-2003)
Prat (1988-1993)
Sugiyama (Not specied)
Zhang (2000-2014)
Overall (
I
2 = 37.80%,
P
= 0.08)
#
% with # of
ES (95%CI) Weight Perforation ERCPS
10 20 30 40 50
Percentage
Perforation cases per ERCP
0.37 (0.10, 1.35)
4.76 (2.05, 10.67)
0.00 (0.00, 1.94)
0.00 (0.00, 3.70)
0.00 (0.00, 2.79)
0.63 (0.11, 3.50)
0.00 (0.00, 7.71)
0.00 (0.00, 8.57)
0.19 (0.09, 0.40)
0.00 (0.00, 8.57)
1.92 (0.34, 10.12)
0.00 (0.00, 35.43)
0.00 (0.00, 4.75)
0.00 (0.00, 0.23)
16.86
6.56
10.05
6.32
7.84
8.79
3.34
3.02
24.76
3.02
3.71
0.60
5.14
100.00
2
5
0
0
0
1
0
0
6
0
1
0
0
538
105
194
100
134
158
46
41
3228
41
52
7
77
D
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

361WJGE
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Volume 10
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Issue 11
|
Study ID
Freeman (Not specied)
Gill (2008-2014)
Inamdar (2009)
Leal (2002-2014)
Li (2000-2008)
Navaneethan (2010)
Overall (
I
-squared = 65.0%,
P
= 0.014)
NOTE: Weights are from random effects analysis
0.144 1 6.93
OR
Overall complications
OR (95%CI)
1.87 (0.98, 3.57)
2.55 (0.94, 6.93)
1.63 (1.37, 1.93)
3.13 (1.50, 6.53)
1.63 (0.64, 4.14)
1.24 (1.11, 1.39)
1.63 (1.27, 2.09)
%
Weight
10.78
5.39
32.79
8.93
6.07
36.04
100.00
E
Study ID
Freeman (Not specied)
Gill (2008-2014)
Inamdar (2009)
Li (2000-2008)
Navaneethan (2010)
Overall (
I
-squared = 2.1%,
P
= 0.394)
NOTE: Weights are from random effects analysis
0.063 1 15.9
OR
Hemorrhage
OR (95%CI)
4.44 (1.66, 11.87)
3.13 (0.62, 15.89)
2.31 (1.55, 3.42)
1.47 (0.24, 9.11)
1.77 (1.33, 2.36)
2.05 (1.62, 2.58)
%
Weight
5.45
2.01
32.38
1.60
58.56
100.00
F
PEP
OR
0.219 1 4.56
Study ID
Inamdar (2009)
Li (2000-2008)
Navaneethan (2010)
Overall (
I
-squared = 65.0%,
P
= 0.057)
NOTE: Weights are from random effects analysis
OR (95%CI)
1.56 (1.28, 1.89)
1.27 (0.35, 4.56)
1.17 (1.04, 1.32)
1.33(1.04, 1.70)
%
Weight
43.51
3.39
53.10
100.00
G
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

patients, and this difference was statistically signicant.
Pooled OR for overall complications was 1.63 (95%CI:
1.27-2.09, p < 0.0001, I2 = 65%). Hemorrhage rate for
patients with cirrhosis was higher than non-cirrhosis,
from a comparison in five studies, with a pooled OR
2.05 (95%CI: 1.62-2.58, p < 0.0001, I2 = 2.1%)
(Figure 2F). PEP rate comparison from three studies
showed a higher incidence in patients with cirrhosis,
with a pooled OR 1.33 (95%CI: 1.04-1.70, p = 0.021,
I2 = 65%) (Figure 2G). Cholangitis rate comparison
between patients with or without cirrhosis, as evaluated
from four studies was not statistically signicant, with a
pooled OR of 1.23 (95%CI: 0.67-2.26, p = 0.511, I2 =
44.3%) (Figure 2H). A perforation rate comparison was
described in only two studies, and hence comparison
analysis could not be obtained.
The power to detect publication bias is low due to the
small number of studies for comparison. Nevertheless,
the p-values were found to be statistically signicant for
overall complications, hemorrhage and PEP. Figure 3
presents a symmetrical funnel plot for the studies used
in comparing overall complications. Heterogeneity is
high due to the different sizes of the studies, with some
studies being small and others being large. The actual
percentage of I2 is described in the results above. The
details regarding the methodological quality of studies
using the Newcastle-Ottawa scale are provided in Table 4.
dIscussIon
In this meta-analysis of studies describing ERCP-re-
lated adverse events in patients with cirrhosis, we
observed a statistically signicant higher rate of overall
adverse events related to ERCP, particularly of PEP
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and hemorrhage. Similar results were observed in the
subset analysis of studies, which allowed a comparison
of ERCP-related adverse events in cirrhosis vs non-
cirrhosis patients. Additionally, the subset analysis
showed a trend towards higher rates of post-procedure
cholangitis in patients with cirrhosis, although that
was not significantly higher than that in non-cirrhosis
patients.
Prior studies have presented variable results when
evaluating adverse events in patients with cirrhosis
undergoing ERCP. Most of the studies in the past have
shown higher rates of hemorrhage in patients with
cirrhosis compared to non-cirrhosis, likely due to a
poor synthetic function of the liver, portal hypertension,
prolonged coagulation times, etc.[5,13-15]. The lowest
rates of hemorrhage (1.1%) in cirrhosis patients were
reported by Adler et al[16] in a large retrospective
study performed at two large centers, including over
500 ERCP procedures, as compared to 4.58% seen
in our meta-analysis. Two major factors potentially
contributing to those lower rates are 1) a smaller per-
centage (15%) of patients receiving sphincterotomy
when compared with other studies that could have
confounded the results, and 2) performance of ERCP
by very experienced operators with a particularly long
history of performing these complicated procedures in
patients with advanced liver disease.
A retrospective matched cohort study of the 2009
National Inpatient Sample with 3228 patients by
Inamdar et al[13] showed an overall ERCP–related
hemorrhage rate of 2.3% in cirrhosis patients, which
is once again lower than the rate demonstrated in
our meta-analysis. However, on the subset analysis,
ERCP-associated hemorrhage for decompensated cir-
November 16, 2018
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Study ID
Inamdar (2009)
Leal (2002-2014)
Li (2000-2008)
Navaneethan (2010)
Overall (
I
-squared = 44.3%,
P
= 0.146)
NOTE: Weights are from random effects analysis
0.714 1 14
OR
Cholangitis
OR (95%CI)
0.98 (0.54, 1.76)
3.78 (1.02, 14.01)
2.26 (0.44, 11.63)
0.77 (0.39, 1.51)
1.23 (0.67, 2.26)
%
Weight
38.46
15.96
11.26
34.32
100.00
H
Figure 2 Forest plot. A: Incidence of ERCP-related hemorrhage = 4.58% (95%CI: 2.77-6.75%, P < 0.01, I2 = 85.92%); B: Incidence of ERCP-related pancreatitis
= 3.68% (95%CI: 1.83%-6.00%, P < 0.01, I2 = 89.50%); C: Incidence of ERCP-related cholangitis = 1.93% (95%CI: 0.63%-3.71%, P < 0.01); D: Incidence of ERCP-
related perforation = 0.00% (95%CI: 0.00%-0.23%, P = 0.08, I2 = 37.8%); E: Meta-analysis of overall complications in six studies comparing cirrhosis and non-cirrhosis
patients; F: Comparison of post-ERCP hemorrhage rates between cirrhosis and non-cirrhosis patients; G: Comparison of post-ERCP pancreatitis (PEP) rates between
cirrhosis and non-cirrhosis patients; H: Comparison of post-ERCP cholangitis rates between cirrhosis and non-cirrhosis patients. ERCP: Endoscopic retrograde
cholangiopancreatography.
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

rhosis was 4.3% when compared to 1.3% in patients
with compensated cirrhosis, and 1% in non-cirrhosis
patients. Another retrospective matched case-control
study by Navaneethan et al[5] using the 2010 National
Inpatient Sample database showed an ERCP-associated
hemorrhage of 2.1% in cirrhosis vs 1.2% in non-cirrhosis
patients. The results from our meta-analysis clearly
demonstrate higher rates of hemorrhage in cirrhosis
patients than previously reported, with a pooled OR of
2.05.
Li et al[17] reported no statistically significant di-
fference between ERCP-associated hemorrhage in
cirrhosis (4.3%) and non-cirrhosis (3%) patients, but
those with Child-Pugh class C had statistically signicant
higher rates of hemorrhage at 25%. Nevertheless,
further information on whether these bleeds were
clinically significant or not was provided. Similarly, a
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study by Park et al[18] described higher rates of ERCP-
related hemorrhage in patients with Child-Pugh class C
(35%) as compared to class A (0%) and B (16%).
Endoscopic sphincterotomy (EST) has been shown
to independently increase the risk of hemorrhage in
cirrhosis as well as non-cirrhosis patients[5,14,19]. The
Navaneethan et al[5] study showed that performing EST
in both compensated and decompensated cirrhosis
patients was an independent risk factor of post-ERCP
bleeding. In the study by Park et al[18], the rates of
bleeding were signicantly lower for endoscopic papillary
balloon dilation in comparison to EST. In addition, one
study also observed lower rates of bleeding when the
ERCPs in cirrhosis patients were performed in medium-
and large-sized hospitals[5]. Since only a limited number
of studies have described hemorrhage or other adverse
events in terms of Child-Pugh class or the type of
intervention, no separate analysis could be obtained in
our meta-analysis[16-18,20].
In terms of PEP, our meta-analysis shows the overall
incidence of cirrhosis to be 3.68% (95%CI: 1.83-6%),
as evaluated from 14 studies. The comparative meta-
analysis using three available studies reveal a higher
rate of PEP in cirrhosis when compared to non-cirrhosis
patients, with a pooled OR of 1.33, which was statisti-
cally signicant as well. While some of the comparison
studies failed to demonstrate a statistically significant
difference for PEP in cirrhosis vs non-cirrhosis patients,
the study by Navaneethan et al[5] described a higher
rate of PEP in cirrhosis patients on univariate analysis,
although this difference fell away once they adjusted
other factors that increased the risk of PEP. These
authors did demonstrate that performing EST was
associated with an increased risk of PEP, although the
cause was unclear, while at the same time placing
prophylactic pancreatic stents was associated with a
decreased risk of PEP[5,14,17,19]. Notably, cirrhosis alone
did not increase the risk of PEP. Patients with alcoholic
November 16, 2018
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|
Ref. Country Study type Cohort/ Case-
control Yr No. of
patients
Newcastle-Ottawa Scale Outcome
Selection Comparability
Navaneethan et al[5] United States Retrospective Case-control 2010 3228 A C ***
Jagtap et al[20] India Retrospective Cohort 2014-2016 134 A **
Adler et al[16] United States Retrospective Cohort 2003-2014 328 A C ***
Inamdar et al[13] United States Retrospective Case-control 2009 1930 A B **
Gill et al[14] Pakistan Retrospective Case-control 2008-2014 100 A C **
Churrango et al[24] United States Retrospective Cohort 2008-2015 194 A C **
Leal et al[19] Spain Retrospective Case-control 2002-2014 158 A C ***
Zhang et al[2] China Retrospective Cohort 2000-2014 77 A C ***
Li et al[17] China Retrospective Cohort 2000-2008 46 A C ***
Ma et al[22] China Retrospective Cohort 2002-2013 41 B C **
Artifon et al[21] Brazil Prospective Case-control Not specied 105 B C ***
Park et al[18] South Korea Prospective/Retrospective Case-control 1998-2003 41 A C ***
Prat et al[25] France Retrospective Cohort 1988-1993 52 A+ C ***
Freeman et al[23] United States Prospective Case-control Not specied 64 A C ***
Sugiyama et al[15] Japan Prospective Cohort Not specied 7 B C ***
Table 4 Methodological quality of included studies using the Newcastle-Ottawa scale
A+: Excellent; A: Very good; B: Good; C: Fair.
Figure 3 Symmetrical funnel plot for the studies used in comparing overall
complications to understand publication bias.
0.5 1 1.5 2 2.5 3
OR for any complication
se (logOR)
0.5 0.4 0.3 0.2 0.1 0
Funnel plot with pseudo 95% condence limits
Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

cirrhosis were noted to have a higher rate of PEP vs
non-alcoholic cirrhosis[5]. Similarly, increased rates of
PEP with EST were seen by Adler et al[16]. Artifon et
al[21] showed that the risk of PEP was decreased with
supra-papillary technique (0%) in comparison with
standard cannulation technique (4.8%). Park et al[18]
suggested lower rates of PEP with endoscopic papillary
balloon dilation in comparison to EST, but the results did
not reach statistical significance. A possible argument
explaining the higher rates of PEP is the conservative
intravenous hydration approach adopted by physicians,
due to concerns of volume overload in decompensated
cirrhosis patients[13].
The rate of post-ERCP cholangitis in cirrhosis pa-
tients from our meta-analysis of 13 studies was 1.93%
(95%CI: 0.63-3.71%), and the comparison analysis
from four studies showed an OR of 1.23 in cirrhosis
patients when compared to non-cirrhosis patients, but
it was not statistically signicant. In the study by Adler
et al[16], the overall rate of post-ERCP cholangitis was
2.8%. However, on the sub-group analysis, the rate
was 5.8% in patients receiving EST as compared to
2.3% in patients with no sphincterotomy, although the
difference was not statistically significant. There was
no comparison group of patients without cirrhosis in
this study. When looking at literature that included a
comparison group of non-cirrhosis patients, the study
by Navaneethan et al[5] demonstrated lower rates of
post-ERCP cholangitis in cirrhosis when compared to
non-cirrhosis, although the difference was not stati-
stically signicant. The reason for this trend is believed
to be the consistent use of prophylactic antibiotics in
cirrhosis patients for spontaneous bacterial peritonitis or
other indications. No statistically significant difference
in cholangitis rates was appreciated in any other
studies[13,14,18,22]. The only study showing higher rate
of cholangitis in the cirrhosis (6.3%) vs non-cirrhosis
group (1.8%) was by Leal et al[19], however the
authors could not provide a plausible explanation for
their observation, and suggested performing further
studies that implement preventive strategies to avoid
cholangitis in patients with cirrhosis.
The perforation rate per our meta-analysis of
13 studies was 0% (95%CI: 0.00-0.23%), and, as
described above, there was no comparison analysis
between the cirrhosis and non-cirrhosis group due
to the small number of studies describing it. Adler et
al[16] reported an overall perforation rate of 0.4%, and
Navaneethan et al[5] reported a perforation rate of 0.2%
in patients with cirrhosis and 0.1% in patients with-
out cirrhosis, although with no statistically signicant
difference.
A small number of studies have described the
relationship of adverse events with the Child-Pugh
score. These studies consistently demonstrated that
the patients with higher Child-Pugh class scores had
more complications overall[16-18,20]. Inamdar et al[13] de-
monstrated a similar risk of adverse events between
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the non-cirrhosis group and patients with compensated
cirrhosis. However, higher rates of adverse events were
observed in patients with decompensated cirrhosis.
Similarly, Adler et al[16] described the post-procedure
adverse events to be lower in Child-Pugh class A (6.1%)
as compared to class B and C combined (11.3%),
which was statistically signicant. Zhang et al[2] noted
no association between the rates of adverse events
when correlated to Child-Pugh class, but elucidated that
patients with higher MELD scores had higher rates of
adverse events.
Higher rates of adverse events have also been
reported depending on maneuvers performed during
the ERCP. Performing EST has been associated with
higher rates of adverse events in comparison to per-
forming stenting alone or endoscopic papillary balloon
dilation[5,14,19,23]. Adler et al[16] described the overall post-
ERCP adverse events to be higher after EST (23.3%),
when compared to patients who did not undergo sphinc-
terotomy (5.6%). Moreover, Freeman et al[23] indicated
EST in cirrhosis patients was associated with excess
morbidity and mortality related to bleeding, with poor
outcomes primarily reported in Child-Pugh class C
patients. Freeman further suggested that ERCP-related
mortality could be reduced by avoiding EST where
dilation or stenting alone is adequate.
Even with the higher rates of overall adverse
events seen in patients with cirrhosis, as described
in our comparison meta-analysis of six studies with
an OR of 1.63 (95%CI: 1.27-2.09), the cholangitis
rates surprisingly did not show a statistically signifi-
cant difference amongst the two groups as has been
described above.
Our present meta-analysis has a few limitations.
First is that the maximum number of cases are derived
from only three studies by Navaneethan et al[5],
Inamdar et al[13] and Adler et al[16]. Secondly, only a few
studies describe adverse events in terms of indications,
the severity of cirrhosis or the type of ERCP-related
interventions. Due to these reasons, we were unable to
obtain a separate sub-group analysis based in relation
to these. The heterogeneity of the overall complication
comparison in cirrhosis vs non-cirrhosis patients is high,
which makes it hard to draw specic conclusions from
the meta-analysis when combined with the low power to
detect bias. This suggests the need for better-controlled
prospective studies in the future for improved clarity of
post-ERCP adverse events in cirrhosis patients. Based
on our experience with ERCP in cirrhosis, we believe
that the adverse events seen in patients with cirrhosis
are similar overall to those seen among unselected
patients undergoing ERCP, although patients with Childs
classes B and C have higher adverse event rates when
compared with those with Childs class A. Patients with
cirrhosis without PSC have signicantly greater adverse
event rates when compared with patients with PSC,
which runs somewhat counter to prevailing thought.
In summary, our meta-analysis clearly demonstrates
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. Meta-analysis of ERCP in cirrhosis

that there is a higher rate of adverse events related to
ERCP (particularly of hemorrhage and PEP) in patients
with cirrhosis than that of patients without cirrhosis,
especially in patients with Child-Pugh class B or C,
and when receiving interventions like EST. Despite
the increased adverse event rates, ERCP remains the
least invasive therapeutic approach for appropriate
indications in pancreatobiliary pathologies for patients
with cirrhosis[13]. A thorough risk/benefit assessment
should be performed in cirrhosis patients prior to ERCP.
artIcle hIGhlIGhts
Research background
Patients with cirrhosis undergoing endoscopic retrograde cholangiopancr-
eatography (ERCP) are believed to have increased risks. However, there
is a paucity of literature describing the indications and outcomes of ERCP
procedures in patients with cirrhosis, especially focusing on adverse events.
Research motivation
ERCP is one of the most commonly performed endoscopic procedures and
is known for its high-risk nature. Performing ERCP in patients with cirrhosis
is not only challenging, but may even be a high-risk endeavor in this setting.
There was therefore a need for a meta-analysis to estimate adverse events
associated with ERCP in cirrhosis patients.
Research objectives
To assess the adverse events associated with ERCP in cirrhosis patients.
Research methods
The preferred reporting items for systematic reviews and meta-analyses
statement and the meta-analysis of observational studies in epidemiology
guidelines were followed. The overall proportion of patients experiencing
any post-procedure adverse events or experiencing specific complications
were estimated using random effects methods designed for the pooling
of proportions. The actual proportions were estimated after the Freeman-
Tukey double arcsine transformation had been applied to the individual study
proportions and standard errors were calculated using the scoring method.
Research results
Individual adverse events included hemorrhage in 4.58% (95%CI: 2.77-6.75%,
I2 = 85.9%), post-ERCP pancreatitis (PEP) in 3.68% (95%CI: 1.83-6.00%, I2 =
89.5%), cholangitis in 1.93% (95%CI: 0.63-3.71%, I2 = 87.1%) and perforation
in 0.00% (95%CI: 0.00-0.23%, I2 = 37.8%).
Research conclusions
There is an overall higher rate of adverse events related to ERCP in patients
with cirrhosis, especially hemorrhage and PEP.
Research perspectives
In the future, a thorough risk/benefit assessment should be performed in
cirrhosis patients prior to ERCP.
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P- Reviewer: Chow WK, Gonzalez-Ojeda A, Kitamura K, Nakai Y,
Sharma SS, Sun SY, Tantau A, Tsuyuguchi T
S- Editor: Ma YJ L- Editor: Filipodia E- Editor: Song H
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Mashiana HS
et al
. Meta-analysis of ERCP in cirrhosis

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